This application is for renewal of research directed toward understanding the molecular and cellular events that mediate olfactory communication in mice, specifically those events underlying complex social behaviors such as aggression, maternal care, and mating. Chemosensation in most mammals is achieved by at least two distinct nasal tissues: the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). The past two years have seen an explosion of studies aimed at understanding the role of the VNO in olfactory communication and pheromone sensing, but a key question remains: What is the nature of the signal transduction mechanism in vomeronasal sensory neurons (VSNs)? Aim 1 of this application is centered on this question. At the same time, evidence is accumulating that sensory neurons in the MOE may also be crucial for pheromone communication in mammals. The identity of the cells and their signaling mechanisms are obscure. Aim 2 addresses this problem. Our main goal is to narrow these critical gaps in our knowledge by determining the cellular and molecular mechanisms that underlie pheromone sensing in the VNO and MOE. To reach this goal we will focus in Aim 1 on an essential component of pheromone transduction in VSNs, the transient receptor potential (TRP) channel TRPC2. A major aim of this application will be to understand the mechanisms underlying activation and regulation of the channels formed by TRPC2, taking advantage of a unique knockout mouse with a targeted deletion in the TRPC2 gene. Members of the TRP channel gene family have recently emerged as essential components in a variety of sensory systems including the senses of taste, heating and balance. Therefore, our results should be of general interest for a better understanding of coding and transduction strategies across different sensory modalities. In Aim 2, we will focus on the function of an enigmatic subpopulation of sensory neurons in the MOE known as GC-D cells, which express the membrane guanylyl cyclase GC-D and several other proteins reminiscent of a cGMP-dependent transduction pathway. We will provide the first systematic analysis of the physiological properties of GC-D cells, including their responses to chemosensory ligands, taking advantage of gene targeted mice that both disrupt the gene that encodes GC-D and specifically label the GC-D cells with a reporter. Specifically, we will test the hypothesis that the GC-D cell system functions as a pheromone detection system necessary for the detection of a limited set of biologically relevant chemical signals.